Many neurons within the medullary raphe project to nuclei that control respiratory motor output. Through release of serotonin (5-HT) and the co-localized neuropeptides substance P and thyrotropin-releasing hormone, these neurons provide an essential tonic drive that maintains ventilation. Many 5-HT neurons are closely associated with large arteries of the brainstem, where they respond to changes in arterial CO2 levels by increasing their firing rate. These properties allow them to play an important role as central respiratory chemoreceptors, causing an increase in ventilation in response to increased CO2 levels and returning CO2 and pH back to normal. Some 5-HT neurons in the midbrain may play a similar role in sensing changes in blood CO2and may induce arousal when CO2 levels increase during sleep. Defects in 5-HT neurons occur in a variety of human diseases and may contribute to abnormalities of respiratory control and blood gas homeostasis.